Origin of Cannabinoid Receptors

Sourcing the Code: Searching for the Evolutionary Origins of Cannabinoid Receptors, Vanilloid Receptors, and Anandamide

AuthorJ.M. McPartland, P. Pruitt

Abstract Two cannabinoid (CB) receptors are known in humans, CB1 and CB2. They are phylogenetically ancient. Studies suggest CB receptors occur in mammals, birds, amphibians, fish, sea urchins, mollusks, leeches, and Hydra vulgaris. The CB receptor genes from some of these animals have been cloned and sequenced. These sequences were used to construct a phylogenetic tree of CB genes. The gene tree is rooted in an ancestral CB gene that predates the divergence of vertebrates and invertebrates. Thus the primordial CB receptor evolved at least 600 million years ago, a date broadly consistent with the Cambrian explosion.

Since then, one clade of invertebrates, the Ecdysozoa, has secondarily lost the genes coding CB receptors. There is no evidence that animals obtained CB genes from other organisms via horizontal gene transfer. We hypothesize that the primordial CB receptor diverged from a related G-protein coupled receptor, and it linked with a pre-existing ligand, anandamide. Anandamide serves as a ligand for CB receptors as well as vanilloid (VR) receptors. VR receptors regulate the sensation of pain, and may also modulate mood and memory. Our phylogenetic analysis suggests that VR receptors evolved before CB receptors, so anandamide first served as a VR ligand. We speculate that CB receptors, lacking se- lective constraints, subsequently acquired a mutation that coupled them with 2-AG. A better understanding of CB and VR receptors man enable us to combine their beneficial effects. Dual-signaling ligands such as anandamide have excellent therapeutic potential as analgesics, vasodilators, and anti-cancer agents.